KHDRBS1
KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the KHDRBS1 gene.
This gene encodes a member of the K homology domain-containing, RNA-binding, signal transduction-associated protein family. The encoded protein appears to have many functions and may be involved in a variety of cellular processes, including alternative splicing, cell cycle regulation, RNA 3'-end formation, tumorigenesis, and regulation of human immunodeficiency virus gene expression.
Function
Sam68 is officially called KHDRBS1. Sam68 is a KH-type RNA binding protein that recognizes UAA direct repeats with relative high affinity. Sam68 is predominantly nuclear and its major function in the nucleus is to regulate alternative splicing by recognizing RNA sequences neighboring the included/excluded exon.Clinical significance
Sam68 influences the alternative splicing of a number of genes central to processes such as neurogenesis and adipogenesis as well as diseases such as spinal muscular atrophy and cancer.Neurogenesis
Sam68 was demonstrated to be involved in the alternative splicing of mRNAs implicated in normal neurogenesis using splicing-sensitive microarrays. Sam68 was also shown to participate in the epithelial-to-mesenchymal transition by regulating the alternative splicing of SF2/ASF. Sam68 was shown to regulate the activity-dependent alternative splicing of the neurexin-1 in the central nervous system with implications for neurodevelopment disorders.Adipogenesis
Sam68 influences alternative splicing of the mTOR kinase contributing to the lean phenotype observed in the Sam68 deficient mice.Spinal muscular atrophy
The role of Sam68 was further highlighted in spinal muscular atrophy, as Sam68 promotes the skipping of exon 7 leading to a non-functional SMN2 protein.Cancer
Sam68 regulates the alternative splicing of a number of cancer-related genes.Direct evidence for the involvement of Sam68 in alternative splicing has been shown in promoting the inclusion of the variable exon 5 in CD44 correlating with cell migration potential. CD44 is a cell surface protein whose expression has been linked to cancer, with its expression predicting prognosis in a number of tumour types. In prostate cancer, Sam68 also interacts with splicing complex proteins KHDRBS3 and Metadherin which also alter CD44 splicing. Subsequently, the knockdown of Sam68 has been shown to delay LNCaP prostate cancer cells proliferation.
In addition, Sam68 in conjunction with hnRNPA1 influences the choice of the alternative 5' splice sites of Bcl-x regulating pro-survival and apoptotic pathways.
The RNA binding activity of Sam68 is regulated by post-translational modifications such that Sam68 is often referred to as a STAR protein by which signals from growth factors or soluble tyrosine kinases, such as Src family kinases, act to regulate cellular RNA processes such as alternative splicing. For example, the Sam68-dependent CD44 alternative splicing of exon v5 is regulated by ERK phosphorylation of Sam68 and Bcl-x alternative splicing is regulated by the p59fyn-dependent phosphorylation of Sam68.
Sam68 is also downstream of the epidermal [growth factor receptor], hepatocyte growth factor /Met receptor, leptin and tumor necrosis factor receptors. While the role of Sam68 in these pathways is slowly emerging much remains to be determined. Sam68 has also been shown to re-localize in the cytoplasm near the plasma membrane, where it functions to transport and regulate the translation of certain mRNAs and regulates cell migration.
The many roles of Sam68 in cancer have been reviewed by Bielli et al.,.